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Comparing strategies to fine-map the association of common SNPs at chromosome 9p21 with type 2 diabetes and myocardial infarction.

ABSTRACT: Noncoding variants at human chromosome 9p21 near CDKN2A and CDKN2B are associated with type 2 diabetes, myocardial infarction, aneurysm, vertical cup disc ratio and at least five cancers. Here we compare approaches to more comprehensively assess genetic variation in the region. We carried out targeted sequencing at high coverage in 47 individuals and compared the results to pilot data from the 1000 Genomes Project. We imputed variants into type 2 diabetes and myocardial infarction cohorts directly from targeted sequencing, from a genotyped reference panel derived from sequencing and from 1000 Genomes Project low-coverage data. Polymorphisms with frequency >5% were captured well by all strategies. Imputation of intermediate-frequency polymorphisms required a higher density of tag SNPs in disease samples than is available on first-generation genome-wide association study (GWAS) arrays. Our association analyses identified more comprehensive sets of variants showing equivalent statistical association with type 2 diabetes or myocardial infarction, but did not identify stronger associations than the original GWAS signals.

SUBMITTER: Shea J

PROVIDER: S-EPMC4096898 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

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Comparing strategies to fine-map the association of common SNPs at chromosome 9p21 with type 2 diabetes and myocardial infarction.

Shea Jessica J Agarwala Vineeta V Philippakis Anthony A AA Maguire Jared J Banks Eric E Depristo Mark M Thomson Brian B Guiducci Candace C Onofrio Robert C RC Kathiresan Sekar S Gabriel Stacey S Burtt Noël P NP Daly Mark J MJ Groop Leif L Altshuler David D

Nature genetics 20110724 8

Noncoding variants at human chromosome 9p21 near CDKN2A and CDKN2B are associated with type 2 diabetes, myocardial infarction, aneurysm, vertical cup disc ratio and at least five cancers. Here we compare approaches to more comprehensively assess genetic variation in the region. We carried out targeted sequencing at high coverage in 47 individuals and compared the results to pilot data from the 1000 Genomes Project. We imputed variants into type 2 diabetes and myocardial infarction cohorts direct ...[more]

PMID: 21775993

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Project description:ObjectiveApproximately 10% of patients undergoing cardiac surgery have perioperative myocardial injury. A recent genome-wide association study identified an association between myocardial infarction in nonsurgical populations and common genetic variants on chromosome 9p21. We hypothesized that these variants are also associated with perioperative myocardial injury after isolated primary coronary artery bypass graft surgery.MethodsIn a prospective observational study of 846 Caucasian patients undergoing primary coronary bypass surgery at 2 US centers, we genotyped 61 linkage-disequilibrium tagging single nucleotide polymorphisms, encompassing 436 kbp of the 9p21 region. A multivariable logistic model was used to adjust for previously identified clinical covariates of perioperative myocardial injury. Perioperative myocardial injury was defined as a postoperative day 1 cardiac troponin I in the top 10th percentile (>9.13 microg/L) of the cohort. Multiple testing of single nucleotide polymorphisms was corrected for with family-wise errors.ResultsPrior myocardial infarction and longer cardiopulmonary bypass time were significant independent predictors of perioperative myocardial injury. Levels of postoperative cardiac troponin I were incrementally increased for each additional copy of the risk alleles of 3 single nucleotide polymorphisms: rs10116277, rs6475606, and rs2383207. Adjusted additive odds ratios ranged between 1.64 and 1.79 (asymptotic P value between 3.7 x 10(-3) and 6 x 10(-4)) and remained significantly associated with perioperative myocardial injury even after accounting for clinical covariates including severity of coronary disease, and multiple comparisons.ConclusionsWe have now demonstrated that common genetic variants in the same 9p21 locus, previously known to be associated with myocardial infarction in nonsurgical populations, are also associated with perioperative myocardial injury after coronary artery bypass grafting. Further investigation is warranted to elucidate functional mechanisms.

Dataset Information

Comparing strategies to fine-map the association of common SNPs at chromosome 9p21 with type 2 diabetes and myocardial infarction.

Publications

Comparing strategies to fine-map the association of common SNPs at chromosome 9p21 with type 2 diabetes and myocardial infarction.

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